Potassium and Hypertension: A State-of-the-Art Review

Abstract

Hypertension is the single most important and modifiable risk factor for cardiovascular morbidity and mortality worldwide. Non pharmacologic interventions, in particular dietary modifications have been established to decrease blood pressure (BP) and hypertension related adverse cardiovascular events. Among those dietary modifications, sodium intake restriction dominates guidelines from professional organizations and has garnered the greatest attention from the mainstream media. Despite guidelines and media exhortations, dietary sodium intake globally has not noticeably changed over recent decades. Meanwhile, increasing dietary potassium intake has remained on the sidelines, despite similar BP-lowering effects. New research reveals a potential mechanism of action, with the elucidation of its effect on natriuresis via the potassium switch effect. Additionally, potassium-substituted salt has been shown to not only reduce BP, but also reduce the risk for stroke and cardiovascular mortality. With these data, we argue that the focus on dietary modification should shift from a sodium-focused to a sodium- and potassium-focused approach with an emphasis on intervention strategies which can easily be implemented into clinical practice.

Hypertension affects 31% of all adults across the world¹ and is the leading cause of preventable mortality.² Dietary modifications proven to decrease blood pressure (BP) in patients with hypertension include restricted alcohol intake, low sodium intake, and more recently higher potassium intake.³ The landmark study in this area was the randomized controlled trial (RCT) DASH (Dietary Approaches to Stop Hypertension) involving 459 adults, including 133 subjects with hypertension.⁴ In this study patients randomized to the DASH diet (which contains 4,700 mg/day of potassium and 3,000 mg/day of sodium) had a modest decrease in systolic BP (SBP) and diastolic BP (DBP) by 5.5 and 3.0 mm Hg respectively as compared to patients on regular diet (P < 0.001 for each).⁴ Importantly, a much larger decrease in SBP and DBP (11.4 mm Hg and 5.5 mm Hg, respectively) was observed in patients with hypertension (SBP ≥140 mm Hg and DBP ≥90 mm Hg).

Different mechanisms have been proposed to explain the benefit of the DASH diet on lowering BP including the natriuretic effect of the high potassium content,⁵ enhanced endothelial production of nitric oxide improving vascular tone⁶ and decreased dietary intake of sodium. We make the case that the potassium content of the DASH diet (about 4,700 mg or 120 mmol/day) has a large, neglected, but possibly major role in the benefit seen with the DASH diet in hypertension. There has been a growing interest in potassium as a potential BP modulator in recent years. Potassium is the most abundant intracellular cation with effects on multiple physiological processes in the body including maintenance of BP. The beneficial effect of a potassium rich diet on BP control and congestive heart failure has been demonstrated even in early studies by Kempner using a rice-fruit diet which was not just extremely low in sodium but also rich in potassium.⁷ Recent literature has provided more evidence regarding mechanisms, and the beneficial effects of potassium on hypertension control. Along with other lifestyle interventions, this is an effective addition to the existing armamentarium to prevent and manage hypertension.

POTASSIUM AND BLOOD PRESSURE: CLINICAL TRIAL EVIDENCE

Several RCTs have been conducted since the aforementioned Kempner study of the rice-fruit diet. A 2014 systematic review of potassium intake conducted by the World Health Organization (WHO) included 22 RCTs with 1,606 participants and 11 cohort studies with 127,038 participants.⁸ The effect of increased potassium intake from the RCTs overall was a reduction of 5.9/3.8 mm Hg. This was greater in subgroups with an achieved potassium intake of 90 to 120 mmol/day (−7.1/4.0 mm Hg). The reduction in BP was otherwise consistent with regards to varying baseline potassium intake, BP measurement device, or method, intervention type (i.e., diet or supplement) and study design. These data have been supported by subsequent RCTs and meta-analysis. Filipinni et al.⁹ conducted a meta-analysis of the effect of potassium supplementation (i.e., non-dietary) on BP and included 25 RCTs involving 1,900 hypertensive subjects with mean ages ranging from 24 to 75 years. The weighted mean difference (WMD) for SBP and DBP was −4.5 (95% CI −5.9 to −3.1) and −3.0 (95% CI −4.8 to −1.1) respectively, with potassium supplementation. Potassium chloride (KCl) was the commonly used supplement type with a median amount of potassium at 64 mmol/day. Similar findings were reported by Poorolajal et al. in a meta-analysis of 23 RCTs and 1,213 participants receiving a potassium supplement.^8,10 The overall BP reduction with potassium supplements was −4.3/−2.5 mm Hg. Potassium supplements were overall well tolerated, with a low rate (<5%) of mild adverse effects, mostly gastrointestinal in nature. In a subgroup analysis, the BP-lowering effect for SBP was greater at a potassium supplement dose >50 mmol/day, and for DBP at >100 mmol/day.

Given that certain potassium rich diets, in particular the DASH diet, do contain more magnesium and alkali content as well, and not just a higher potassium, a small double blind crossover RCT compared potassium citrate, KCl and potassium magnesium citrate vs. placebo in 30 participants.^10,11 Interestingly, the authors reported that KCl supplementation only induced a significant reduction in nighttime SBP compared with placebo (116 ± 12 vs. 121 ± 15 mm Hg, respectively, P< 0.01 vs. placebo), whereas potassium magnesium citrate and potassium citrate had no significant effect in the same subjects (118 ± 11 and 119 ± 13 mm Hg, respectively, P > 0.1 vs. placebo). In contrast, another crossover RCT of 15 participants not only reported significant BP-lowering with both KCl and potassium citrate compared to placebo, but little difference between the two preparations (mean difference 1.6 mm Hg, P = 0.39).¹² There is intriguing ancillary data on improving salt sensitivity in a small study of 38 healthy normotensive men (24 Blacks and 14 Whites). There was a dose-dependent suppression of salt sensitivity (Blacks > Whites) when dietary potassium was increased within normal range up to a maximum of 120 mmol/day.¹³

In summary, there is strong evidence from RCTs, and meta-analysis of RCTs (as summarized in Table 1), that increasing potassium intake, whether by diet or with supplements, is effective in lowering BP.

POTASSIUM AND HYPERTENSION-RELATED CARDIOVASCULAR OUTCOMES

Unfortunately, unlike the literature with potassium and BP, very few RCTs have been sufficiently powered for hard clinical endpoints with potassium. The exception is with RCTs of salt substitutes (see more on that in a section later in the review). The WHO systematic review on the effect of potassium also included 11 cohort studies (127,038 participants) reporting all-cause mortality, cardiovascular (CV) disease, stroke, or coronary artery disease.⁸ An inverse association was reported between potassium intake and risk of incident stroke (RR 0.76, 95% CI 0.66–0.89). Associations between potassium intake and incident CV disease (RR 0.88, 95% CI 0.70–1.11) or coronary heart disease (RR 0.96, 95% CI 0.78–1.19) were not statistically significant. For all-cause mortality, the review had only two studies which could not be combined. Interestingly, one of the included studies, the Scottish Heart Health Study, compared prediction by 27 different factors in men and women of coronary heart disease events, coronary deaths, and all-cause mortality by random sampling of residents aged 40–59 years, including 11,629 men and women between the years 1984–1987.¹⁷ The study reported an “unexpectedly powerful” protective relation of dietary potassium on all-cause mortality. The relative risk of all-cause mortality in those with dietary potassium intake at 80th percentile (compared to reference of 20th percentile) was 0.58 in men, and 0.48 in women (both P < 0.001).

SAFETY OF INCREASING POTASSIUM INTAKE

There is a concern that increasing potassium intake in the diet will result in adverse effects, principally hyperkalemia. This concern is especially important in individuals with a decreased ability to excrete potassium, such as those with chronic kidney disease (CKD), heart failure or those on concomitant medications which impaired potassium excretion, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists. On the other hand, a potassium rich diet usually contains fresh fruits, vegetables, whole grains and plant-based protein which supply a high amount of fiber and alkali which are favorable for the CKD population as constipation and metabolic acidemia often contribute to the hyperkalemia.^12,18 The risk of hyperkalemia with potassium intake should be highest in those on hemodialysis, who have virtually little to no ability to excrete potassium via their kidneys. However, observational studies support a higher consumption of fruits and vegetables being associated with the lower mortality in hemodialysis populations.¹⁹ In the DIETary intake, death and hospitalization in adults with end-stage kidney disease treated with HemoDialysis (DIET-HD) study of 8,043 adults on hemodialysis, dietary potassium intake was not associated with serum levels of potassium (0.03; 95% CI, −0.01 to 0.07 mEq/L per 1 g/day higher dietary potassium intake), prevalence of hyperkalemia (odds ratio, 1.11; 95% CI, 0.89–1.37 per 1 g/day higher dietary potassium intake), or all-cause mortality (hazard ratio, 1.00; 95% CI, 1.00–1.00 and hazard ratio, 1.01; 95% CI, 0.96–1.06).^19,20 The poor correlation between dietary potassium and serum potassium in these populations was also demonstrated in a meta-analysis of five studies involving 9,181 patients (r = 0.06, 95% CI, 0.02–0.10).¹⁸ In contrast to dietary potassium (which may be plant-based, or with a high amount of alkali) which seems to have a lower propensity to cause hyperkalemia, one could still be concerned about a potassium supplement. An RCT of a potassium supplement (KCl 40 mmol/day for 2 weeks) in 191 patients with a mean glomerular filtration rate (GFR) of 31 mL/min/1.73 m² reported a small but significant increase in serum potassium (from 4.3 ± 0.5 to 4.7 ± 0.6 mmol/L, P < 0.001).^18,21 The 21 participants (11%) that developed hyperkalemia (plasma potassium 5.9 ± 0.4 mmol/L) were all older and had higher baseline plasma potassium. Another small crossover trial of 29 patients with stage 3 CKD (GFR 30–59 mL/min/1.73 m²) compared the effect of a fixed potassium diet of 40 or 100 mmol per day, based on the DASH diet with differing amounts of potassium.²² The mean serum potassium was higher by 0.21 mmol/L (P = 0.003), and 2 patients (7%) developed hyperkalemia defined as serum K ≥5.5 mmol/L. Thus, there is indeed a possible small risk of biochemical hyperkalemia with very high intakes of potassium in the form of supplements for people with CKD. Notably, however, the relationship between higher serum potassium and clinical outcomes is not linear, but rather U-shaped, with a nadir at a serum potassium ~ 4.9 mmol/L, and higher mortality particularly not just with serum potassium >5.5 mmol/L but also at serum potassium <4.0 mmol/L.²³ Additionally, people living with CKD have a high risk of CV death, which is often driven by hypertension, which has to be taken into account when estimating the net effect, as discussed later.²⁴

POTASSIUM AND BLOOD PRESSURE: MECHANISMS

Human kidneys have adapted during evolution to conserve sodium and excrete potassium. This was beneficial in prehistoric humans who consumed a diet rich in potassium and poor in sodium.²⁵ With the current modern Western diet containing predominantly processed foods rich in sodium, this previously homeostatic adaptation becomes detrimental. Potassium deficit induces intracellular acidosis and enhances sodium-hydrogen exchanger type 3 in the proximal tubule and thick ascending limb of the loop of Henle where the bulk of filtered sodium is reabsorbed.²⁶ Long term potassium depletion stimulates the sodium pump (Na⁺–K⁺ exchanger) in the medullary collecting duct (CD) of the kidney and increases the intracellular sodium to potassium ratio.²⁷ In vascular smooth muscle cells (VSMC), this increases the intracellular calcium via the sodium–calcium exchanger type 1 (by the high sodium) and via voltage dependent calcium channels in the membrane and sarcoplasmic reticulum (by the low potassium causing membrane depolarization).²⁸ A high potassium diet causes membrane hyperpolarization in the VSMC leading to opposite effects and promotes vasodilation.²⁹ In fact the anti-hypertensive effect of thiazide diuretics in the long term involves vasodilation due to depletion of cellular sodium stores and redistribution of potassium into cells.³⁰ Central nervous system effects of potassium have also been reported to alter sympathetic outflow and affect BP.³¹

A more recently proposed mechanism of potassium regulation by the kidney and its effect on BP involves the with-no-lysine (WNK) kinases and potassium switch mechanism in the distal convoluted tubule (DCT).³² WNK kinases are serine threonine kinases which act in a kinase cascade to phosphorylate and activate the sodium chloride co-transporter (NCC) and the related sodium potassium-2 chloride cotransporters (NKCC1 and NKCC2) via the downstream kinases, Oxidative stress response protein type 1—[OSR1] and Sterile 20 [STE20] proline alanine-rich kinase [SPAK].³³ The predominant WNK kinases in the kidney include the Long-form of WNK1, L-WNK1, the kidney specific WNK1 (KS WNK1), and WNK4. WNK4 is responsible for controlling NCC activity via SPAK, which binds to and directly phosphorylates NCC.^34,35 WNK4 is also required for phosphorylation of NKCC2 in the TAL, but this is mediated by the downstream kinase, OSR1.^35–38 KS-WNK1, primarily expressed in the DCT, does not have a kinase domain but is necessary for coalescence of signaling proteins into WNK bodies, important for NCC phosphorylation.³⁹ Gain-of-function WNK-SPAK signaling constitutively activates NCC, causing Gordon’s Familial Hyperkalemic Hypertension.^40–42 Consequently, the major focus of attention on WNK kinases in physiology has been on the DCT and NCC.

WNK kinases are inhibited by the binding of intracellular chloride and potassium, a property that allows the WNK-SPAK cascade in the DCT to be especially sensitive to membrane voltage, and small physiologic changes in extracellular potassium.^43–45 When plasma potassium falls, Kir4.1/5.1 potassium channels on the basolateral surface of DCT sense and transmit the change by membrane hyperpolarization, which in turn drives chloride and potassium out of the cell and off the inhibitory binding sites, activating WNK4, SPAK, and NCC. The phosphorylation dependent activation of NCC in the DCT increases sodium reabsorption in this segment of the nephron and raises BP. When plasma potassium goes up, membrane depolarization favors chloride and potassium binding, inhibiting the WNK kinases. This is accompanied by activation of a protein phosphatase, PP1a, which binds to and inactivates the apical NCC.

Inactivation of the apical NCC decreases the sodium reabsorption in the DCT and promotes distal sodium delivery to the aldosterone sensitive distal nephron, namely the CNT and CD, promoting more potassium excretion (Figure 1).⁴⁶ Thus the “renal potassium switch” turns on the thiazide sensitive NCC in response to low potassium intake (as seen with modern diet) and turns off with high potassium intake. The existence of the potassium switch mechanism in humans was confirmed in a recent crossover study, wherein oral potassium supplementation resulted in lower urinary extracellular vesicle levels of NCC and phosphorylated NCC among healthy adults on a high sodium, low potassium diet.⁴⁷

SODIUM AND BLOOD PRESSURE: THE EVIDENCE AND THE LIMITATIONS

Consumption of excess sodium is indeed associated with increased risk of high BP and its CV complications.^48,49 Several mechanism have been described to explain sodium mediated hypertension including renal salt retention, increased sympathetic stimulation, salt induced vasodysfunction,⁵⁰ effect on arterial stiffness,⁵¹ and immune mechanisms involving activation of dendritic cells with production of free radicals, activation of T-cells and subsequent migration of these T-cells to various organs causing vascular inflammation and enhanced renal absorption of sodium.⁵² About 50% of hypertensive patients and 25% of normotensive patients exhibit salt sensitivity characterized by parallel changes in BP and salt intake.

The effect of a reduction in dietary sodium on lowering BP is clear and unequivocal. Apart from the aforementioned DASH trial, a systematic review of 37 RCTs also reported a reduction in resting SBP by 3.4 mm Hg (95% CI 2.5–4.3) and DBP by 1.5 mm Hg (95% CI 1.0–2.1).⁵³ The reduction was more marked in those with baseline hypertension (SBP—4.1 mm Hg, 95% CI 3.0–5.2). However, the data for reduced dietary sodium intake preventing adverse CV outcomes is far less impressive. The data from RCTs in this systematic review lacked sufficient power to detect a relation between sodium intake and CV outcomes or mortality.⁵³ They did report a benefit from a pooled meta-analysis of 14 cohort studies, which reported an association between increased sodium intake and increased risk of stroke but no significant relation with risk of incident CV disease or coronary heart disease. Conversely, a subsequent large epidemiological study with 101,945 participants from five continents reported that the lowest risk of major CV events including mortality was found with a dietary intake of sodium between 3 and 6 g daily.^53,54 In contrast, as compared with an estimated potassium intake of less than 1.5 g per day, higher potassium intake was associated with a reduced risk of the composite outcome of death and major CV events. Sodium and potassium intake were extrapolated from a fasting morning spot sample for urinary sodium or potassium. Though this study has been criticized for using spot urine samples rather than 24-h urine for assessing dietary intake, this approach would introduce random misclassification of exposure, which, if anything, would not introduce systematic bias but would bias any results towards the null. Nevertheless, observational data, especially, for an exposure such as dietary intake, are susceptible to selection bias and confounding, and cannot be extrapolated into an expected benefit to be seen with an intervention.

Despite substantial evidence in favor of sodium restriction at least for BP reduction and the push for decreasing sodium intake in several guidelines over the years, sodium intake in most populations has not budged. A systematic review of 38 studies conducted using 24 h urine sodium in the US from 1957 to 2003 reported that the study years were not associated with any significant change in sodium excretion (coefficient for study years in 10-year increments in multivariate random-effects model = 154 mg Na/24 h/10 years; 95% CI −140, 448).⁵⁵ The 2023 WHO report on this topic estimates that the global average salt intake is more than twice the recommended level, with the average person consuming about 10.8 g of salt per day (corresponding to about 4.3 g sodium or 188 mmol/day) in their diet, as opposed to the 5 g (2 g sodium or 100 mmol/day) recommended by the WHO.⁵⁶ The report also makes clear that the world is off-track to achieve the WHO global target of reducing sodium intake by 30% by 2025. This observation is not surprising once one considers the efficacy to effectiveness gap in this field. The trials of reducing dietary sodium, such as the DASH diet, were all mostly feeding trials, and not trials of behavior change.⁵⁷ In a systematic review that included RCTs which reported a significant reduction in sodium intake with a 24-h urine sodium sample, only four RCTs provided sufficient details of the intervention used. All four used interventions that were not feasible for use in routine practice, such as a 5-day inpatient cooking training, or provision of food from a research kitchen. Indeed, a low sodium diet is likely more expensive in most settings, hence the findings of the WHO report are not surprising and, to some extent, expected.^58,59

IMPLEMENTATION SCIENCE: ROLE OF SALT SUBSTITUTES

Traditional salt is sodium chloride (NaCl) with the salt source varying around the world. In countries like India, China, and Peru, among others, up to 75% of the sodium intake comes from the salt added during food preparation in the household.⁶⁰ However in countries like the United States, 70% of the sodium is from commercially processed and restaurant foods, and not salt added at the time of cooking in the household or from the salt shaker.⁶¹ This aspect needs to be recognized while designing interventions for reduction of sodium intake.

Salt-substitution involves replacing a portion of NaCl with a potassium salt, typically KCl, thus decreasing the sodium content. A study looking at the worldwide use of salt substitutes (also called low sodium salts) found the use of 87 varieties of salt across 47 countries, of which 60% are in the high income group.⁶² The amount of sodium replaced varied from 12% to 100% depending on the geographical region and the manufacturer. The price of these salts varies from United States dollar (USD) $0.46/kg to $87/kg, which is 1.1–14.6 times the cost of regular salt (potassium costs about four times more than sodium). Unfavorable effects of salt substitutes include alteration in taste to bitter and metallic as shown in a study with the participants perceiving an increase in saltiness.⁶³ Other studies have shown no change in palatability at lower KCl content (up to 25% of the salt), with higher KCl content being too metallic in taste.^64,65 Addition of nutritionally acceptable minerals like magnesium chloride or magnesium sulfate to the salt has also been reported to improve the flavor.⁶⁶

Effect of salt-substitution on blood pressure

Several trials have been conducted with potassium containing salt substitutes, and in a systematic review that included 13 RCTs, there was a significant effect of the salt substitute on the SBP (mean difference −5.6, 95% CI −7.1 to −4.1) and DBP (mean difference −2.9, 95% CI −3.9 to −1.8).⁶⁷ Two subsequent cluster RCTs further confirm these findings. In a trial of 2,376 participants from six villages in Peru, the use of potassium-substituted salt (25% KCl) reported an average reduction of 1.3/0.8 mm Hg in BP, but perhaps more importantly, a 51% lower risk of developing hypertension in those who did not have baseline hypertension.⁶⁸ In the Salt Substitute and Stroke Study (SSaSS), 20,995 participants from 600 villages were enrolled, with a similar salt substitute intervention (75% NaCl with 25% KCl). At the end of the 5-year follow up, BP was lower with the intervention by an average of −3.3/0.7 mm Hg.^16,68 A recent cluster RT involving residential elderly care facilities (mean age of residents 71 years) in China showed that use of salt substitute (62.5% NaCl, 25% KCl and 12.5% food ingredients) vs. usual salt lowered SBP (−7.1 mm Hg, CI −10.5 to −3.8 mm Hg) and DBP (−1.9 mm Hg, CI −3.6 to −0.02 mm Hg) and was associated with fewer CV events (HR 0.84, 95% CI 0.63–1.13).⁶⁹

Effect of salt substitutes on CVD and mortality

In SSaSS the primary outcome was fatal or non-fatal stroke, which was significantly lower in the salt-substitute group (29.1 events vs. 33.7 events per 1,000 person-years; rate ratio [RR] 0.86, 95% CI 0.77–0.96) at the end of 5 years.¹⁶ Salt-substitution was also beneficial in terms of secondary outcomes of major CV events (RR 0.87, 95% CI 0.80–0.94), all-cause mortality (RR 0.88, 95% CI 0.82–0.95), death from vascular causes (RR 0.87, 95% CI 0.79–0.96) and non-fatal acute coronary syndrome (RR 0.70, 95% CI 0.52–0.93).¹⁶ Another cluster RCT from Taiwan also reported a significant benefit of a salt substitute (49% KCl, 49% NaCl and 2% additives) on CV mortality (age adjusted HR 0.49, 95% CI 0.37–0.95) when compared to the usual salt group at 31 months of follow up.⁷⁰

Safety of salt substitutes: effect on serum potassium

The concern with using salt substitutes is whether this might also cause harm, chiefly hyperkalemia, as mentioned previously. A systematic review and meta-analysis of 20 studies (1,216 participants) looking at the effect of oral potassium supplementation (average of 45 mmol/day) on serum potassium levels and renal function showed a small but significant increase in potassium levels (WMD 0.14 mmol/L, 95% CI 0.09–0.19) with no significant effect on serum creatinine levels (WMD 0.30 μmol/L, 95% CI −1.19 to 1.78).⁷¹ The effect was more pronounced in those with concomitant potassium rising drug therapy (0.17 mmol/L versus 0.11 mmol/L, P = 0.05). There were no serious side effects related to hyperkalemia reported in any of the included trials. While 16 of these trials were done in patients with hypertension, 2 trials were done in patients with hypokalemia while on diuretics and none of them included patients with renal impairment. In the SSaSS, there was no difference in the rate of hyperkalemia between the two groups.¹⁶ However, the actual incidence of hyperkalemia with salt substitutes among CKD populations is difficult to estimate due to the exclusion of the high risk population from clinical trials, for example, the SSaSS excluded individuals with severe renal impairment, which was undefined.^72,73 This has consequences if the salt substitute is to be rolled out not on an individual level, but at a population scale, or by the food industry. An intriguing Markov model analysis factors that the higher dietary potassium from a salt substitute would lower BP and consequently lower the risk of CV death but additionally also increases rates of hyperkalemia and causes some mortality from it. Overall, the model reports a net benefit in lives saved, not only in the overall population, but also in the CKD population, despite the risk of hyperkalemia^23,74 (see Figure 2).

IMPLEMENTATION SCIENCE FOR DIETARY CHANGES IN HYPERTENSION

We have reviewed the data showing that increasing dietary potassium intake effectively reduces BP, and observational data also support its association with lower rates of stroke and mortality. Decades of guidelines and media outreach have not budged sodium consumption meaningfully at the population level. Rather than flog failed policies and interventions focusing on sodium, this is now an opportunity to pivot to potassium. It is possible, though unproven, that increasing the dietary consumption of a nutrient, such as potassium, might be easier than removing a nutrient that is entrenched in our food supply and dietary habits, as is the case with sodium.^75,76 Additionally, salt substitutes (with higher potassium content) lower BP and decrease rates of stroke and mortality, based on trial evidence. The U.S. Food and Drug Administration in 2020 provided guidance to food manufacturers of its intent to exercise enforcement discretion for the name “potassium salt” in the ingredient statement on food labels as an alternative to “potassium chloride” to better inform consumers that it is a salt substitute.⁷⁷ It is also considering amendment of the standards of identity (SOIs) to permit the use of sodium chloride substitutes in foods, with the goal of providing food manufacturers the ability to meet its voluntary sodium reduction targets. This would allow greater incorporation of potassium, replacing sodium, in the food industry and downstream directly in the food supply. Thus, we would not be as dependent on behavior change which is much more finicky and hard to modify.^59,77 In settings where food preparation mostly occurs in the household, apart from choosing foods rich in potassium, replacing table salt with a potassium-enriched salt (already available in the market) could be a simple and effective strategy.

Substituting sodium chloride with KCl, at levels like the SSaSS trial, should be considered as a relatively safe and palatable approach. Most people consume about half of the daily recommended amount of potassium, so the substitution would also help achieve adequate levels of potassium in the diet with all the benefits to BP and cardiovascular health. Considering available evidence, development of hyperkalemia in at-risk populations is low, but not zero. More trials are needed to test whether the benefits to cardiovascular health outweigh risks. In the meantime, we favor labeling foods to inform consumers about the type of sodium substitutes and amount of potassium. It is worthwhile reiterating that the vast majority of the population with high BP have mild uncomplicated hypertension, with no impairment of renal handling of potassium. In these settings, there is little concern about the safety of an increase in potassium intake. See Table 2 for a summary of the data on sodium and potassium with respect to evidence and implementation.

RESEARCH NEEDS

Despite the literature discussed which strongly supports the incorporation of potassium at a higher status among the non-pharmacological means of managing hypertension, significant gaps remain. Though we speculate that increasing dietary potassium could be easier than reducing dietary sodium, this remains to be proven, which we should find out in a few years with ongoing RCTs. With respect to potassium supplements, the data are mixed on the BP-lowering effect of different potassium salts (e.g., KCl, potassium citrate, or potassium magnesium citrate) and also whether the hyperkalemic potential of these might differ in at-risk patients. Lastly, though modeling studies seem to suggest that population wide use of a potassium-enriched salt substitute will have a net benefit, even in patients with CKD, this remains an issue of concern, and requires follow up studies in jurisdictions where the use of these substitutes becomes widespread.

CONCLUSION

In summary, potassium is a hitherto neglected ion in the diet–hypertension axis. Epidemiologic, trial, and mechanistic research support its role as significant for BP control. Perhaps implementing a potassium-focused diet strategy might be more successful than the last few futile decades which had a sole focus on sodium.

Acknowledgments

SH and MR receive research salary support from the Department of Medicine, University of Ottawa. SH has received research grant support from the Lotte & John Hecht Memorial Foundation for studying potassium in hypertension. GLH is supported by the Lorna Jocelyn Wood Chair in Kidney Research.

REFERENCES